Typhoid control key to prevent gallbladder cancer in India

Controlling bacterial infections responsible for typhoid fever could dramatically reduce the risk of gallbladder cancer in India and Pakistan, according to scientists including an Indian researcher.
The findings establish for the first time the causal link between bacterial infection and gallbladder cancer, explaining why this type of cancer is rare in the West but common in India and Pakistan, where typhoid fever is endemic.
Public policy changes inspired by this research could have an immediate impact on preventing a type of cancer that currently has a very poor prognosis, researchers said.
"While viruses are among the established causal factors for particular cancers, bacteria are largely ignored as direct contributors," said senior study author Jacques Neefjes of the Netherlands Cancer Institute.

"Accepting that bacterial infections can directly contribute to cancer formation makes these tumours in principle preventable," said Neefjes.
"If Salmonella Typhi infections are cured immediately with antibiotics and chronic infections are prevented, or if vaccination programmes to eradicate S Typhi work, we would expect a major reduction in the incidence of a tumour that represents the third most common gastrointestinal tumour in India and Pakistan," Neefjes said.

Gallbladder cancer is hard to diagnose in its early stages because there are no signs or symptoms. By the time the cancer is detected, it is often too late to save patients.
Because the prognosis of gallbladder cancer is so poor, Neefjes, Tiziana Scanu of the Netherlands Cancer Institute, and Gopal Nath of Banaras Hindu University set out to gain insight into how to combat this tumour by identifying causal factors underlying its unique global distribution.

The researchers quickly zeroed in on S Typhi because this typhoid-causing bacterium is endemic in India and has been associated with gallbladder cancer in epidemiological studies.
Moreover, proteins that Salmonella injects into host cells activate cancer-related signalling pathways called AKT and MAPK, which support not only bacterial infection and survival, but also the growth and proliferation of cancer cells.
To explore the role of S Typhi in cancer in the new study, Neefjes and Scanu compared tumour samples from Indian and Dutch patients with gallbladder cancer.
While both groups showed signs of AKT and MAPK activation and an inactive, mutant TP53 cancer gene, only Indian patients showed strong evidence of S Typhi infection and over-activating mutations in a cancer gene called c-Myc.

To mimic the features of the tumour samples from India, the researchers transplanted Salmonella-infected cells with mutations affecting TP53 and c-Myc activity into mice.
These mice later developed tumours, demonstrating that Salmonella causes cancer in genetically at-risk hosts as a result of the collateral damage induced by its normal infection cycle.
The study was published in the journal Cell Host & Microbe.